Mouse double minute 2 homolog (MDM2) is a protein that is encoded by the MDM2 gene. MDM2 functions as an E3 ubiquitin ligase and as a negative regulator of the tumor suppressor protein, p53, by ubiquitinating and targeting p53 for degradation (8). MDM2 affects the cell cycle, apoptosis and tumorigenesis through interaction with other proteins, including retinoblastoma (RB) (50).
Genome-wide association studies, such as The Cancer Genome Atlas projects, show that most cancers are genetically heterogeneous. A few recurrent alterations/mutations are integral to the development and progression of a tumor, while a host of other changes can substantially alter its phenotype, affecting progression and impacting both patient prognosis and the efficacy of therapy (1-5). Ninety percent of well-differentiated and dedifferentiated liposarcomas (WD/DDLS) have amplification of genes on chromosome segment 12q13-15, in a background of karyotypes that are widely variable and, in many instances, highly complex. The 12q13-15 amplification is associated with overexpression of the oncogenes, MDM2 and CDK4, and the corresponding translated proteins are thought to promote liposarcomagenesis (6).
CDK4 promotes cell proliferation by catalyzing phosphorylation and inactivation of RB (7), and MDM2 suppresses oncogene-induced apoptosis or senescence by inactivating p53 (8). Drugs have been developed that specifically target these potential drivers and the effect of these targeted agents in patients with a variety of tumors has been an active area of investigation. However predicting the efficacy of these drugs on patient outcome has been problematic, because of the extensive molecular crosstalk between p53 and RB pathways and the genomic heterogeneity of the tumors examined (9, 10).